Phospholipid-analogous compounds

ABSTRACT

The present invention relates to compositions comprising a water-insoluble pharmaceutically active ingredient or a substance having low water solubility, and a compound represented by Structural Formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             in which A is: 
           
         
       
    
                         
The present invention further relates to methods of solubilizing substances of low water solubility, and methods of preparing compositions suitable for intravenous administration.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 10/377,617 filed Mar. 4, 2003, which is a divisional application ofU.S. application Ser. No. 10/025,778, filed Dec. 26, 2001, now U.S. Pat.No. 6,545,169, which is divisional application of U.S. application Ser.No. 09/486,039, filed May 17, 2000, now U.S. Pat. No. 6,344,576, whichis a national stage filing under 35 U.S.C. § 371 of PCT/EP98/05252,filed Aug. 18, 1998, which claims priority under 35 U.S.C. § 119 toforeign application 197 35 776 (DE), filed Aug. 18, 1997. Thedisclosures of all of the above identified applications are herebyincorporated by reference.

The invention relates to novel phospholipid-analogous compounds whichcan be employed as liposome constituents for transportingpharmaceuticals, as solubilizers for pharmaceuticals of low solubilityin water and also as active ingredients themselves for disorders such ascancer and leishmaniosis, to liposomes containing these novel compounds,to pharmaceutical compositions which contain these liposomes, and toprocesses for producing pharmaceuticals.

The invention relates in particular to phosphatidyl compounds whichcontain a defined hydrophilic radical, and to liposomes which have ashortened or lengthened lifespan in the serum and can be taken upspecifically by particular cells, for example tumour cells.

The retention time of conventional liposomes in the serum is up to 5hours. However, it is desirable, especially when liposomes are used ascarriers of active pharmaceutical ingredients, for the liposomeretention time in the blood circulation to be as long as possible, butespecially in conjunction with uptake in selected target cells.

Hence the so-called stealth liposomes which have a lengthened lifespanwere developed. These stealth liposomes have a structure based onphosphatidyl compounds which contain an extended polyethylene glycolresidue. The polyethylene glycol residue proved to be most effective forthe desired lengthened lifespan with molecular weights between 2000 and3000. A considerable disadvantage of these stealth liposomes and of thephosphatidyl compounds with polyethylene glycol residue is, however,that they are not accurately defined compounds because the polyethyleneglycol residues have different chain lengths. However, the so-calledstealth liposomes always have, as a consequence of the phosphateradical, a negative surface charge in the liposome membrane. The objectof our own earlier patent application 196 22 224.9 was therefore toprovide compounds which increase the lifespan of liposomes and have acomposition which can be stated accurately, likewise using phosphateesters and thus negative charges.

An object of the present invention is, by contrast, to provide compoundswhich avoid this negative surface charge and link the oligoglycerol orsugar residues by a nitrogen atom into the structure. The positivecharge on the nitrogen residue balances the negative charge on thephosphate, or even overcompensates when 2 nitrogen atoms are used in themolecule. This object is achieved according to the invention by acompound of a general formula I

where R₁ and R₂ are, independently of one another, hydrogen, a saturatedor unsaturated acyl or alkyl radical which can optionally be branchedor/and substituted, where the total of the carbon atoms in the acyl andalkyl is 16 to 44 C atoms,

-   s is an integer from 0 to 8,-   c is a radical of a primary or secondary alcohol of the formula RO—,    where R is a saturated or unsaturated alkyl radical, mainly with cis    double bond, of from 12 to 30 carbon atoms,-   n is an integer from 2 to 8,-   R₃-   a can be 1,2-dihydroxypropyl or-   b can be alkyl with 1 to 3 C atoms when z is >0 or-   c can be alkyl with 1 to 3 carbon atoms when n≠2 and z=0,-   m is 1 or 2,-   x is an integer from 0 to 8,-   y is 1 for z=1 to 5 or    -   is 1 to 4 for z=1-   z is an integer from 0 to 5.

Preferred compounds are those where

m=1, n=2, x=0, z≠0, and R₃ is an alkyl radical, do not applysimultaneously.

The structural elements used in the substances described herein can bevaried at will and adapted to suit the particular use.

It is possible via structural parameter A to vary mainly the apolarportions of the molecules, for example via the chain length of the fattyacids and of the alkyl radicals. A modification of the polar portions ispossible via the phosphate group, the nitrogen atom and theoligoglycerols linked thereto.

The compounds embraced by the general formula I have excellentbiological properties and are used as

-   1) liposome constituents for specific accumulation of active    ingredients in target cells,-   2) solubilizers for substances which are difficult to administer    intravenously such as, for example, Taxol,-   3) active ingredients for cancer and protozoal diseases.

The compounds which have particular importance for the variousapplications are now described in detail. There are overlaps in thisbecause disubstituted glycerols with the structural feature A may haveboth membrane-stabilizing properties (R₁+R₂>20 C atoms) andmembrane-destabilizing properties (R₁+R₂<20 C atoms). In particular, theboundary regions between membrane- and micelle-formers may be of specialinterest here.

It is common to all the structures that the novel molecules are simpleto prepare, this being possible by reacting primary or secondary amineswith epoxides. Thus,1,2-dipalmitoyl-sn-glycero-3-phospho(N-methyl)ethanolamine withbenzylglycidol results, after catalytic debenzylation and methylation onnitrogen, in a phospholipid with a lecithin-like structure which is usedas liposome constituent.

Compounds with only one long alkyl or acyl chain have other interestingproperties if they are linked via primary or secondary amines toepoxides, as is evident from the description hereinafter. They areexcellent solubilizers for active ingredients which are difficult toadminister intravenously and are in fact direct active ingredients forcancer and leishmaniasis.

The stepwise assembly, on which this invention is based, of thehydrophilic radicals of the phosphatidyl compounds of the formula Imakes it possible to take an accurately defined composition of thecompounds.

Thus the compound of the formula I according to the invention does notcomprise a mixture of different molecules of indefinite composition andchain length; on the contrary, it is possible to obtain specifically adesired structure. This means that, if the desired product is anN,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)ammoniumderivative with y=1 and z=2 in formula I, the compound is chemicallydefined and contains no portions with y=1 and z=1 or y=1 and z=3 etc.Hydroxypropyl derivatives having a wholly defined chain length andessentially free of other chain lengths are preferably used.

The compound of the formula I is, according to the invention, ahomogeneous compound of defined structure. The compound is preferablymore than 99% homogeneous in relation to the value of z. However, it isalso possible to provide the compound with a homogeneity of more than99.9% in relation to the value of z.

The compound preferably comprises hydroxypropyl derivatives on thenitrogen with 1 to 5 hydroxypropyl units, preferably with 1 to 3hydroxypropyl units. Preferred in this connection are 1,3-linked linearoligoglycerol residues which are linked via a 2-hydroxypropyl radical tothe nitrogen atom.

The radical for A=c with the formula RO— is derived from the primary orsecondary alcohol. When RO— is derived from a secondary alcohol,radicals with-the oxygen on the C₂, C₃ or C₄ atom are preferred.

The radicals R¹ and R² are according to the invention preferablyindependently of one another hydrogen, a saturated or unsaturated acylor alkyl racial which may optionally be branched or/and substituted,where the total of the carbon atoms in the acyl and alkyl is between 16and 44.

The invention further relates to liposomes which contain phospholipidsor/and alkylphospholipids, where appropriate cholesterol and 1 to 50 mol% of a compound of the general formula I.

The phospholipids or/and alkylphospholipids can be, for example,diacylglycerophospho compounds of defined structure. It is generallypossible to employ these constituents of the lipids as compounds ofdefined structure.

In the case where y>1, the radical —CH₂(CHOH)_(y)—CH₂—OH is preferablyderived from sugar alcohols which have 3 hydroxyl groups for y=2, 4hydroxyl groups for y=3 and 5 hydroxyl groups for y=4. Examples of suchradicals are mannitol derivatives for y=4, lyxitol derivatives for y=3and threitol derivatives for y=2.

The liposomes according to the invention have a distinctly modifiedhalf-life in the blood circulation. The liposomes with m=1 are neutralto the outside and show increased retention times in the blood, whilethe liposomes with m=2 circulate for only a very short time as aconsequence of the excess positive charge in the membrane.

The invention further relates to a pharmaceutical composition whichcontains the liposomes described above and one or more activepharmaceutical ingredients entrapped in the liposomes, where appropriatetogether with pharmaceutically customary diluents, excipients, carriersand bulking agents.

It is possible as a rule to use as active ingredients all activeingredients which can in fact be introduced into the plasma by means ofliposomes. Preferred groups of active ingredients are, on the one hand,cytostatics, in particular anthracycline antibiotics such as, forexample, doxorubicin, epirubicin or daunomycin, with doxorubicin beingparticularly preferred. Further preferred cytostatics are idarubicin,hexadecylphosphocholine,1-octadecyl-2-methyl-rac-glycero-3-phosphocholine, 5-fluorouracil,cis-platinum complexes such as carboplatin and Novantrone, andmitomycins.

Further preferred groups of active ingredients are immunomodulatingsubstances such as, for example cytokines, with particular preferencebeing given among these in turn to the interferons and, in particular,α-interferon, substances with antimycotic activity (for exampleamphotericin B) and active ingredients for protozoal diseases (malaria,tyrpanosomal and leishmania infections). Taxol is likewise preferred asactive ingredient.

Another preferred group of active ingredients are lytic activeingredients like those described in DE 41 32 345 A1. Preference is givento miltefosin, edelfosin, ilmofosin and SR162-834. Particular preferenceis given to alkyphosphocholines also with extended alkyl chains, forexample erucylphosphocholine and erucylphosphocholines with increasedphospho-nitrogen distance.

The present invention further relates to the use of liposomes accordingto the invention for producing an antitumour composition, in which casethe active ingredient is particularly preferably doxorubicin.

The present invention furthermore relates to the use of the liposomesaccording to the invention for producing a composition for influencingcell proliferation, in which case the active ingredient is a cytokine,particularly preferably α-interferon.

The liposomes according to the invention are prepared by methods knownper se using apparatus customary for this-purpose. It is possibletypically to convert a solution containing the various components of theliposome, including 1 to 50 mol % of a compound of the formula I, into alipid suspension which is then forced under high pressure throughnozzles or through perforated plates, it being possible to control thesize of the resulting liposomes by the size of the orifices in theperforated plate. Suitable measures for converting a lipid suspensioninto liposomes are known to the skilled person. Preferably, 5 to 55 mol% of a compound of the general formula I are converted with 35 to 60 mol% of cholesterol and 40 to 60 mmol % of phospholipids or/andalkylphospholipids into a lipid suspension which is then converted bysuitable measures in a manner known per se into liposomes. Such knownprocesses can also be used to produce a pharmaceutical preparation whichcontains the liposomes according to the invention and one or more activepharmaceutical ingredients. For entrapping water-insoluble activeingredients, the active ingredient is dissolved together with the lipidconstituents while, for entrapping water-soluble active ingredients, anaqueous solution containing the water-soluble active ingredient is addedto the lipid film.

The initial phospholipids are produced by processes described in theliterature (DE 31 30 867 A1: Eibl et al., Chem. Phys. Lipids 28 (1981)),1-4 41 (1986), 53-63 and 47 (1988), 47-53. It is possible here inparticular to have recourse to processes described in the PCT/EP97/00749application of 17.02.1997. Thus, the compounds according to theinvention of the formula I can be prepared in the following way:

Example (A=a; n=2; m=1; y=1; z=2)

(Reaction of 1,2-dipalmitoyl-sn-glycero-3-phospho(N-methyl)ethanolaminewith 1,2-isopropylidene-glyceroglycidol)

Corresponding reactions can be carried out to afford compounds withn=3-10, m=1, y=1, z=1-5. Starting compounds for x=2 and 3 are cephalinsand N-methylcephalins, whose preparation has been described in detail.The reactions with the corresponding glycidols, whose preparation isdescribed in the German patent application “Phosphatidyloligoglycerine”19622224, leads to the required products, the addition being carried outin a 2-phase system of THF-Na₂CO₃/NaHCO₃ 1:1 (0.5 M in H₂O; pH 9-10).However, no hydrolysis of the fatty acid esters is observed at these pHvalues.

To prepare the dioleoyl compounds it is necessary to prepare1,2-dioleoyl-sn-glycero-3-phospho-(N-methyl)ethanolamine. This isachieved by the following reaction scheme:

Unsaturated compounds are generally prepared analogously.

It is possible correspondingly to prepare compounds with n=4-8 becausethe corresponding terminal alkanolamines can be purchased and can beconverted into the N-BOC-protected compounds.

Examples of a synthesis of liposome constituents are described below todemonstrate the experimental breadth of the present application. It ispossible, as is evident from the examples, to prepare any fatty acidester and alkyl ether combinations which vary in chain length, number ofcis double bonds and degree of branching.

The RF values of the exemplary compounds 1 to 279 were determined in thesystem CHCl₃/CH₃OH/glacial acetic acid/H₂O=100/60/20/5 parts by volume.They are grouped very close together, specifically as follows:

RF Compound No. 0.10-0.15 129-135 0.15-0.20 117-128, 167, 172, 209-2160.20-0.25  70-84, 98-116, 151-166, 197-208 0.25-0.30  45-69, 136-150,183-196, 262-272 0.30-0.35  25-44, 173-182, 255-261, 273-279 0.35-0.40 1-24 0.40-0.45  85-97 0.30-0.40 217-240 0.20-0.30 241-254

EXAMPLES A) Preparation oferucoyl-1,3-propanediol-phospho-N,N,N-trimethylpropylammonium Example176

Erucoyl-1,3-propanediol

1,3-Propanediol, 153 g (MW 76.1; 2 mol) is dissolved in 1 l of THF and,after addition of 60 g of triethylamine (MW 101.2, 0.6 mol) and 7.3 g of4-dimethylaminopyridine (MW 122.2, 0.06 mol), equilibrated at 20° C. ina water bath. While stirring continuously, 178 g of erucoyl chloride (MW357.0; 0.5 mol) in 500 ml of THF are slowly added dropwise so that thetemperature in the reaction mixture does not exceed 30° C. The dropwiseaddition is followed by warming at 30° C. for 30 minutes and thenaddition of 1.5 l of diisopropyl ether and 1.5 l of 1N HCl. Aftervigorous shaking and phase separation, the upper ether phase is washedonce again with 1% NaCl solution and evaporated in vacuo at 45° C. Theresidue is taken up in 2 l of hexane and cooled to −20° C. The whitecrystals are filtered off with suction and dried in vacuo. The yield ofpure erucoyl-1,3-propanediol is 123 g (MW 396.7; 62%). The substance ispure by thin-layer chromatography (Rf value 0.3 in ether/pentane/aceticacid 200/200/2 parts by volume).

Microanalysis

C₂₉H₄₅₀₃ calc.: C 75.70; H 12.20; O 12.10 found: C 75.81; H 12.16; =,−

Erucoyl-1,3-propanediol-phospho-N-methylpropylammonium

Phosphorus oxychloride, 24.2 g (MW 153.33; 0.16 mol) in 15 ml of THF iscooled to 0° C. in an ice bath. A solution of erucoyl-1,3-propanediol,60 g (MW 396.7; 0.15 mol) and 17.2 g of triethylamine (MW 101.19; 0.17mol) in 250 ml of THF is added dropwise with stirring so that thetemperature in the reaction mixture does not exceed 150° C. After thedropwise addition of the solution, the temperature of the reactionmixture is brought to 20° C. and stirred for a further 30 minutes.

The conversion of the formed erucoyl-1,3-propanediol-phosphoric aciddichloride into the target product takes place by reaction withN-methylpropanolamine via an intermediate six-membered ring. This isdone by adding a solution of 16 g of N-methylpropanolamine (MW 89.14;0.18 mol) and 35.4 g of triethylamine (MW 101.19; 0.35 mol) in 250 ml ofTHF dropwise to the stirred reaction mixture in such a way that thetemperature does not exceed 35° C. After the dropwise addition, thereaction mixture is kept at 25° C. for 30 minutes. The precipitatedtriethylamine hydrochloride is filtered off. The filtrate contains theintermediate (Rf 0.25 in CHCl₃/ethyl acetate 1:1, parts by volume) andis converted by adding 60 ml of 2 N HCl with ring opening intoerucoyl-1,3-propanediol-phospho-N-methylpropylammonium (Rf 0.45 inCHCl₃/CH₃OH/glacial acetic acid/H₂O 100/80/10/5, parts by volume). TheTHF solution of the product is mixed with 200 ml of 0.2 M sodiumphosphate solution (pH—8.0) and adjusted to pH 6-7. The product isprecipitated by adding 1 l of acetone, and the crystals are isolated byfiltration with suction at 4° C.Erucoyl-1,3-propanediol-phospho-N-methylpropylammonium is sometimesslightly impure. Chromatography on silica gel with CHCl₃/CH₃OH/H₂O canbe employed for purification. The yield of pure product—based onerucoyl-1,3-propanediol—is 65 g (MW 547.8; 79%).

Microanalysis

C₂₉H₅₈NO₆P calc.: C, 63,59; H, 10,67; N, 2,56; O, 17,53; P, 5,66 found:C, 63,34; H, 10,49; N, 2,49; O, -; P, 5,59

Erucoyl-1,3-propanediol-phospho-N,N,N-trimethylzropylammonium

Erucoyl-1,3-propanediol-phospho-N-methylpropylamine, 54.8 g (MW 547.8,0.1 mol) is mixed with 800 ml of THF and 83 g of K₂CO₃ (0.6 mol) in 800ml of H₂O. The mixture is heated to 50° C. to result in a two-phasesolution. While stirring vigorously, 74.5 g of methyl toluenesulphonate(MW 186.23; 0.4 mol) in 200 ml of THF are added dropwise, and themixture is boiled under reflux. The reaction is complete after 60minutes. Erucoyl-1,3-propanediol-phospho-N,N,N-trimethylpropylammoniumis precipitated as product (Rf value 0.1 in CHCl₃/CH₃OH/glacial aceticacid/H₂O 100/80/10/5, parts by volume) from the THF phase with 1.2 l ofacetone, and the precipitate is taken up in 300 ml of CHCl₃, filteredand again precipitated with 1.2 l of acetone; If the product is notquite pure, chromatography on silica gel with —CHCl₃/CH₃OH/H₂O can beemployed for purification. The yield of pure product—based on theN-methyl compound—is 49 g (MW 575.8; 85%).

Microanalysis

C₃₁H₆₂NO₆P calc.: C, 64,66; H, 10,85; N, 2,43; O, 16,67; P, 5,38 found:C, 64,38; H, 10,81; N, 2,39; O, -; P, 5,27

B) Preparation oferucoyl-1,3-propanediol-phospho-N,N-dimethyl-N-(hydroxypropyldihydroxypropyl)-propylammoniumExample 155

This compound can be prepared by using the intermediateerucoyl-1,3-propanediol-phospho-N-methyl-propylammonium. It is convertedin a reaction firstly with an epoxide and immediately further methylatedto give the final product.Erucoyl-1,3-propanediol-phospho-N-methylpropylammonium, 54.8 g (MW547.8; 0.1 mol) is mixed with 800 ml of THF and 83 g of K₂CO₃ (0.6 mol)in 800 ml of H₂O and heated to 50° C. to result in a two phase solution.While stirring vigorously, a solution of 21 g of1,2-isopropylideneglycero-3,1-glycidol (MW 188.2; 0.11 mol) in 200 ml ofTHF is added dropwise, and the temperature is raised to 60° C. Thereaction mixture is boiled under gentle reflux for 2 hours, and 37 g ofmethyl toluenesulphonate (MW 196.23; 0.2 mol) in 100 ml of THF areadded. The reaction is complete after boiling under reflux for 2 hours.The THF phase is substantially evaporated at 45° C., and the residue isheated with 300 ml of 70% acetic acid at 60-65° C. to remove theisopropylidene protective group. A mixture of 1 l of CHCl₃, 1 l of CH₃OHand 1 l of 1% strength NaCl solution is added to the reaction mixtureand, after thorough shaking, the solvent is removed from the lower CHCl₃phase in vacuo. The residue is taken up in 400 ml of CHCl₃ andprecipitated with 1.6 l of acetone. Chromatography on silica gel withCHCl₃/CH₃OH/H₂O can be employed for purification. 46 g oferucoyl-1,3-propanediol-phospho-N,N-dimethyl-N-(hydroxy-3,1-dihydroxypropyl)propylammonium(MW 709.94; 65%) are obtained.

All the compounds detailed hereinafter can be prepared by these generalmethods for preparing compounds both hydroxylated on the nitrogen andnon-hydroxylated.

Examples of Two-Chainglycerophospho-N,N-dimethyl-N-di-hydroxypropylalkylammonium Compounds

(A = a; n = 2-6; R₃, CH₃; m = 1; x = 0; y = 1; z = 1) Formel I

1) 1,2-Dipalmitoyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxypropyl-ethylammonium (n = 2) (R₁, R₂ = CO—OCH₂)₁₄—CH₃)C₄₂H₈₄NO₁₀P (794.10) 2)1,2-Distearoyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxyproyl-ethylammonium (n = 2) (R₁, R₂ = CO—(CH₂)₁₆—CH₃) C₄₆H₉₂NO₁₀P(850.20) 3) 1,2-Dimyristoyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxypropyl-ethylammonium (n = 2) (R₁, R₂ = CO—(CH₂)₁₂—CH₃)C₁₈H₇₆NO₁₀P (737.99) 4)1,2-Dierucyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxypropyl-ethylammonium (n = 2) (R₁, R₂ =CO—(CH₂)₁₁—CH═CH—(CH₂)₇—CH₃) C₅₄H₁₀₄NO₁₀P (958.39) 5)1,2-Dioleoyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxyproyl-ethylammonium (n = 2) (R₁, R₂ = CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃)C₄₆H₈₈NO₁₀P (846.17) 6) 1-Stearoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N-dihydroxyproyl-ethylammonium (n = 2) (R₁ = CO—(CH₂)₁₆—CH₃; R₂ =CO—(CH₂)₁₇—CH═CH—(CH₂)₂—CH₃) C₄₆H₉₀NO₁₀P (848.19) 7)1-Stearoyl-2-myristoyl-sn-glycero-3-phospho-N,N-di-methyl-N-dihydroxypropyl-ethylammonium (n = 2) (R₁ = CO—(CH₂)₁₆—CH₃; R₂= CO—(CH₂)₁₂—CH₃) C₄₂H₈₄NO₁₀P (794.10) 8)1-Stearoyl-2-lauroyl-sn-glycero-3-phospho-N,N-di-methyl-N-dihydroxyproyl-ethylammonium (n = 2) (R₁, = CO—(CH₂)₁₆—CH₃; R₂= CO—(CH₂)₁₀—CH₃) C₄₀H₈₀NO₁₀P (766.04) 9)1-Lauroyl-2-stearoyl-sn-glycero-3-phospho-N,N-di-methyl-N-dihydroxypropyl-ethylammonium (n = 2) (R₁—CO—(CH₂)₁₀—CH₃; R₂ =CO—(CH₂)₁₆—CH₃) C₄₀H₈₀NO₁₀P (766.04) 10)1-Erucoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N-dihydroxypropyl-ethylammonium (n = 2) (R₁ =CO—(CH₂)₁₁—CH═CH—(CH₂)₇—CH₃) (R₂ = CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃)C₅₀H₉₆NO₁₀P (902.28) 11) 1-Oleoyl-2-erucyl-sn-glycero-3-phospho-N,N-di-methyl-N-dihydroxypropyl-ethylammonium (n = 2) (R₁ =CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃) (R₂ = CO—(CH₂)₁₁—CH═CH—(CH₂)₇—CH₃)C₅₀H₉₆NO₁₀P (902.28) 12)1,2-Dipalmitoyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxypropyl-ethylammonium (n = 3) (R₁, R₂ = Cl—(CH₂)₁₄—CH₃)C₄₃H₈₆NO₁₀P (808.12) 13)1,2-Dierucyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxypropyl-ethylammonium (n = 3) (R₁, R₂ =CO—(CH₂)₁₁—CH═CH—(CH₂)₇—CH₃) C₅₅H₁₀₆NO₁₀P (972.413) 14)1,2-Dioleoyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxypropyl-ethylammonium (n = 3) (R₁, R₂ =CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃) C₄₇H₉₀NO₁₀P (860.20) 15)1-Stearoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N-dihydroxypropyl-ethylammonium (n = 3) (R₁ = CO—(CH₂)₁₆—CH₃; R₂= CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃) C₄₇H₉₂NO₁₀P (862.21) 16)1-Stearoyl-2-lauroyl-sn-glycero-3-phospho-N,N-di-methyl-N-dihydroxypropyl-ethylammonium (n = 3) (R₁ = CO—(CH₂)₁₆—CH₃; R₂= CO—(CH₂)₁₀—CH₃) C₄₁H₈₂NO₁₀P (780.07) 17)1,2-Dipalmitoyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxypropyl-butylammonium (n = 4) (R₁, R₂ = CO—(CH₂)₁₄—CH₃)C₄₄H₈₈NO₁₀P (822.15) 18)1,2-Dioleoyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxypropyl-butylammonium (n = 4) (R₁, R₂ =CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃) C₄₈H₉₂NO₁₀P (874.23) 19)1,2-Dierucyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxypropyl-butylammonium (n = 4) (R₁, R₂ =CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃) C₅₆H₁₀₈NO₁₀P (986.44) 20)1-Stearoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N-dihydroxpropyl-butylammonium (n = 4) (R₁ = CO—(CH₂)₁₆—CH₃; R₂ =CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃) C₄₈H₉₄NO₁₀P (876.24) 21)1-Stearoyl-2-lauroyl-sn-glycero-3-phospho-N,N-di-methyl-N-dihydroxypropyl-butylammonium (n = 4) (R₁ = CO—(CH₂)₁₆—CH₃; R₂= CO—(CH₂)₁₀—CH₃) C₄₂H₈₄NO₁₀P (794.10) 22)1,2-Dipalmitoyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxypropyl-hexylammonium (n = 6) R₁, R₂ = CO—(CH₂)₁₄—CH₃) C₄₂H₈₄NO₁₀P(794.10) 23) 1,2-Dioleoyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxpropyl-hexylammonium (n = 6) (R₁, R₂ = CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃)C₅₀H₉₆NO₁₀P (902.28) 24)1,2-Dierucyl-sn-glycero-3-phospho-N,N-dimethyl-N-di-hydroxypropyl-hexylammonium (n = 6) (R₁, R₂ =CO—(CH₂)₁₁—CH═CH—(CH₂)₇—CH₃) C₅₈H₁₁₂NO₁₀P (1014.49)

Examples of Two-Chainglycerophospho-N,N-dimethyl-N-(2-hydroxy-propyl-3,1-O,O-dihydroxypropyl)-alkylammoniumCompounds

(A = a; n = 2-6; R₃, O₃; m = 1; x = 0; y = 1; z = 2) Formula I

25) 1,2-Dipalmitoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-dihydroxy-pro- pyl)ethylammonium (n = 2) (R₁; R₂ =CO—(CH₂)₁₄—CH₃) C₄₅H₉₀NO₁₂P (868.18) 26)1,2-Distearoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-dihydroxy-pro- pyl)ethylammonium (n = 2) (R₁; R₂ =CO—(CH₂)₁₆—CH₃) C₄₉H₉₈NO₁₂P (924.28) 27)1,2-Dierucoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-dihydroxypropyl)-eth- ylammonium (n = 2) (R₁; R₂ =CO—(CH₂)₁₁—CH═CH—(CH₂)₇—CH₃) C₅₇H₁₁₀NO₁₂P (1032.47) 28)1,2-Dioleoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-dihydroxypropyl)ethyl-am- monium (n = 2) (R₁; R₂ =CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃) C₄₉H₉₄NO₁₂P (920.25) 29)1-Stearoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxy-pro- pyl)ethylammonium (n =2) (R₁ = CO—(CH₂)₁₆—CH₃; R₂ = CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃) C₄₉H₉₆NO₁₂P(922.27) 30) 1-Stearoyl-2-lauroyl-sn-glycero-3-phospho-N,N-di-methyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxy-pro- pyl)ethylammonium (n =2) (R₁ = CO—(CH₂)₁₆—CH₃; R₂ = CO—(CH₂)₁₀—CH₃) C₄₃H₈₆NO₁₂P (840.12) 31)1-Erucoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxy-pro- pyl)ethylammonium (n =2) (R₂ = CO—(CH₂)₁₁—CH═CH—(CH₂)₇—CH₃; R₂ = CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃)C₅₃H₁₀₂NO₁₂P (976.36) 32)1-Oleoyl-2-erucoyl-sn-glycero-3-phospho-N,N-di-methyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxy-pro- pyl)ethylammonium (n =2) (R₁ = CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃; R₂ = CO—(CH₂)₁₁—CH═CH—(CH₂)₇—CH₃)C₅₃H₁₀₂NO₁₂P (976.36) 33)1,2-Dipalmitoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-dihydroxy-pro- pyl)propylammonium (n = 3) (R₁, R₂ =CO—(CH₂)₁₄—CH₃) C₄₆H₉₂NO₁₂P (882.20) 34)1,2-Distearoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-dihydroxy-pro- pyl)propylammonium (n = 3) (R₁, R₂ =CO—(CH₂)₁₆—CH₃) C₅₀H₁₀₀NO₁₂P (938.31) 35)1,2-Dierucoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-dihydroxypropyl)propyl-am- monium (n = 3) (R₁, R₂=CO—(CH₂)₁₁—CH═CH—(CH₂)₇—CH₃) C₅₈H₁₁₂NO₁₂P (1046.49) 36)1,2-Dioleoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-dihydroxypropyl)-pro- pylammonium (n = 3) (R₁, R₂ =CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃) C₅₀H₉₆NO₁₂P (934.28) 37)1-Stearoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxy-pro- pyl)propylammonium (n =3) (R₁ = CO—(CH₂)₁₆—CH₃; R₂ = CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃) C₅₀H₉₈NO₁₂P(936.29) 38) 1-Stearoyl-2-lauroyl-sn-glycero-3-phospho-N,N-di-methyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxy-pro- pyl)propylammonium (n =3) (R₁ = CO—(CH₂)₁₆—CH₃; R₂ = CO—(CH₂)₁₀—CH₃) C₄₄H₈₈NO₁₂P (854.15) 39)1,2-Dioleoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-dihydroxypropyl)butyl-am- monium (n = 4) (R₁, R₂ =CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃) C₅₁H₉₈NO₁₂P (948.30) 40)1,2-Dierucoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-dihydroxypropyl)butyl-am- monium (n = 4) (R₁, R₂ =CO—(CH₂)₁₁—CH═CH—(CH₂)₇—CH₃) C₅₉H₁₁₄NO₁₂P (1060.52) 41)1-Stearoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxy-pro- pyl)butylammonium (n =4) (R₁ = CO—(CH₂)₁₆—CH₃; R₂ = CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃) C₅₁H₁₀₀NO₁₂P(950.32) 42) 1-Stearoyl-2-lauroyl-sn-glycero-3-phospho-N,N-di-methyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxy-pro- pyl)butylammonium (n =4) (R₁ = CO—(CH₂)₁₆—CH₃; R₂ = CO—(CH₂)₁₀—CH₃) C₄₅H₉₀NO₁₂P (868.175) 43)1,2-Dioleoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-dihydroxypropyl)hexyl-am- monium (n = 6) (R₁, R₂ =CO—(CH₂)₇—CH═CH—(CH₂)₇—CH₃) C₅₃H₁₀₂NO₁₂P (976.358) 44)1,2-Dierucoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-dihydroxypropyl)hexyl-am- monium (n = 6) (R₁, R₂ =CO—(CH₂)₁₁—CH═CH—(CH₂)₇—CH₃) C₆₁H₁₁₈NO₁₂P (1088.57)

Examples of Two-chainglycerophospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-2-hydroxypropyl-3,1-O,O-dihydroxypropyl)alkylammoniumCompounds

(A = a; n = 2-8; R₃, CH₃; m = 1; x = 0; y = 1; z = 3) Formula I

45) 1,2-Dipalmitoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-2-hydroxypropyl-3,1-di- hydroxypropyl)ethylammonium(n = 2) (N-(2-hydroxypropyl-3,1-O,O-2-hydroxypropyl-3,1-di-hydroxypropyl) is abbreviated in the following text to N—(HP₁-HP₂—diHP₃)C₄₈H₉₆NO₁₄P (942.25) 46) 1,2-Distearoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁HP₂—diHP₃)eth- ylammonium (n = 2) C₅₂H₁₀₄NO₁₄P (998.36) 47)1,2-Dierucoyl-sn-glycero-3-phospho-N,N-di- methyl-N—(HP₁-HP₂—diHP₃)eth-ylammonium (n = 2) C₆₀H₁₁₆NO₁₄P (1106.54) 48)1,2-Dioleoyl-sn-glycero-3-phospho-N,N-di- methyl-N—(HP₁-HP₂—diHP₃)eth-ylammonium (n = 2) C₅₂H₁₀₀NO₁₄P (994.33) 49)1-Stearoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)ethylammonium (n = 2) C₅₂H₁₀₂NO₁₄P (996.35) 50)1-Stearoyl-2-lauroyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)ethylammonium (n = 2) C₄₆H₉₂NO₁₄P (914.20) 51)1,2-Palmitoyl-2-lauroyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)ethylammonium (n = 2) C₄₄H₈₈NO₁₄P (886.15) 52)1,2-Dipalmitoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)pro- pylammonium (n = 3) C₄₉H₉₈NO₁₄P (956.28)53) 1,2-Distearoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)pro- pylammonium (n = 3) C₅₃H₁₀₆NO₁₄P (1012.39)54) 1,2-Dierucoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)pro- pylammonium (n = 3) C₆₁H₁₁₈NO₁₄P (1120.57)55) 1,2-Dioleoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)pro- pylammonium (n = 3) C₅₃H₁₀₂NO₁₄P (1008.36)56) 1-Stearoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)propylammonium (n = 3) C₅₃H₁₀₄NO₁₄P (1010.37)57) 1-Stearoyl-2-lauroyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)propylammonium (n = 3) C₄₇H₉₄NO₁₄P (928.23) 58)1-Palmitoyl-2-lauroyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)propylammonium (n = 3) C₄₅H₉₀NO₁₄P (900.17) 59)1,2-Dipalmitoyl-sn-glycero-3-phospho-N,N-di- methyl-N—(HP₁-HP₂—diHP₃)bu-tylammonium (n = 4) C₅₀H₁₀₀NO₁₄P (970.31) 60)1,2-Distearoyl-sn-glycero-3-phospho-N,N-di- methyl-N—(HP₁-HP₂—diHP₃)bu-tylammonium (n = 4) C₅₄H₁₀₈NO₁₄P (1026.41) 61)1,2-Dierucoyl-sn-glycero-3-phospho-N,N-di- methyl-N—HP₁-HP₂—diHP₃)bu-tylammonium (n = 4) C₆₂H₁₂₀NO₁₄P (1134.60) 62)1,2-Dioleoyl-sn-glycero-3-phospho-N,N-di- methyl-N—(HP₁-HP₂—diHP₃)bu-tylammonium (n = 4) C₅₄H₁₀₄NO₁₄P (1022.38) 63)1,2-Dipalmitoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)hexyl- ammonium (n = 6) C₅₂H₁₀₄NO₁₄P (998.36)64) 1,2-Distearoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)hexyl- ammonium (n = 6) C₅₆H₁₁₂NO₁₄P (1054.47)65) 1,2-Dierucoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)hexyl- ammonium (n = 6) C₆₄H₁₂₄NO₁₄P (1162.65)66) 1,2-Dioleoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)hexyl- ammonium (n = 6) C₅₆H₁₀₈NO₁₄P (1050.44)67) 1,2-Distearoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)oc- tylammonium (n = 8) C₅₈H₁₁₆NO₁₄P (1082.52)68) 1,2-Dioleoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)oc- tylammonium (n = 8) C₅₈H₁₁₂NO₁₄P (1078.49)69) 1,2-Dierucoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂—diHP₃)oc- tylammonium (n = 8) C₆₆H₁₂₈NO₁₄P (1190.70)

Examples of Two-chainglycerophospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-2-hydroxypropyl-3,1-O,O-2-hydroxypropyl-3,1-O,O-dihydroxypropyl)alkylammoniumCompounds

(A = a: n = 2, 3; R₃, O₃; m = 1; x = 0, y = 1; z = 4) Formula I

70) 1,2-Dipalmitoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(2-hy-droxypropyl-3,1-O,O-2-hydroxypropyl-3,1-O,O-hydroxypropyl-3,1-dihydroxypropyl)ethyl-am- monium (n = 2)[N-[2-hydroxypropyl-3,1-O,O-2-hydroxypropyl-3,1-O,O-di-hydroxypropyl-3,1-O,O-dihydroxypropyl] is abbreviated in the followingtext to N—(HP₁-HP₂-HP₃—diHP₄). C₅₁H₁₀₂NO₁₆P (1016.33) 71)1,2-Distearoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁-HP₂-HP₃—diHP₄)eth- ylammonium (n = 2) C₅₅H₁₁₀NO₁₆P (1072.44)72) 1,2-Dierucoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁-HP₂-HP₃—diHP₄)eth- ylammonium (n = 2) C₆₃H₁₂₂NO₁₆P (1180.62)73) 1,2-Dioleoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂-HP₃—diHP₄)eth- ylammonium (n = 2) C₅₅H₁₀₆NO₁₆P(1068.41) 74) 1-Stearoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂-HP₃—diHP₄)eth- ylammonium (n = 2) C₅₅H₁₀₈NO₁₆P(1070.42) 75) 1-Stearoyl-2-lauroyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂-HP₃—diHP₄)ethylammonium (n = 2) C₄₉H₉₈NO₁₆P (988.28)76) 1-Palmitoyl-2-lauroyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂-HP₃—diHP₄)ethylammonium (n = 2) C₄₇H₉₄NO₁₆P (960.23)77) 1,2-Dipalmitoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂-HP₃—diHP₄)pro- pylammonium (n = 3) C₅₂H₁₀₄NO₁₆P(1030.36) 78) 1,2-Distearoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂-HP₃—diHP₄)propyl- ammonium (n = 3) C₅₆H₁₁₂NO₁₆P(1086.47) 79) 1,2-Dierucoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂-HP₃—diHP₄)pro- pylammonium (n = 3) 80)1,2-Dioleoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂-HP₃—diHP₄)pro- pylammonium (n = 3) C₅₆H₁₀₈NO₁₆P(1082.43) 81) 1-Stearoyl-2-lauroyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂-HP₃—diHP₄)propyl- ammonium (n = 3) C₅₀H₁₀₀NO₁₆P(1002.31) 82) 1-Stearoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂-HP₃—diHP₄)propylammonium (n = 3) C₅₆h₁₁₀NO₁₆P(1084.45) 83) 1-Arachinoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂-HP₃—diHP₄)propylammonium (n = 3) C₅₈H₁₁₄NO₁₆P(1112.50) 84) 1-Behenoyl-2-oleoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁-HP₂-HP₃—diHP₄)propylammonium (n = 3) C₆₀H₁₁₈NO₁₆P(1140.56)

Examples of Two-chain Glycerophospho Compounds not Hydroxylated on theNitrogen

(A = a; n = 2-6; m = 1; x = 1; z = 0) Formula I

85) 1,2-Dioleoyl-sn-glycero-3-phospho-N,N,N-trimethyl-pro- pylammoniumC₄₅H₈₆NO₈P (800.15) 86)1,2-Dioleoyl-sn-glycero-3-phospho-N,N,N-trimethyl-bu- tylammoniumC₄₆H₈₈NO₈P (814.17) 87)1,2-Dioleoyl-sn-glycero-3-phospho-N,N,N-trimethyl-pentyl- ammoniumC₄₇H₉₀NO₈P (828.20) 88)1,2-Dioleoyl-sn-glycero-3-phospho-N,N,N-trimethyl-hexyl- ammoniumC₄₈H₉₂NO₈P (842.23) 89)1-Stearoyl-2-oleoyl-sn-glycero-3-phospho-N,N,N-tri- methylpropylammoniumC₄₅H₈₈NO₈P (802.16) 90)1-Stearoyl-2-oleoyl-sn-glycero-3-phospho-N,N,N-tri- methylbutylammoniumC₄₆H₉₀NO₈P (816.19) 91)1-Palmitoyl-2-lauroyl-sn-glycero-3-phospho-N,N,N-tri-methylpropylammonium C₃₇H₇₄NO₈P (691.97) 92)1-Oleoyl-2-lauroyl-sn-glycero-3-phospho-N,N,N-tri- methylpropylammoniumC₃₉H₇₆NO₈P (718.00) 93)1-Erucoyl-2-oleoyl-sn-glycero-3-phospho-N,N,N-tri- methylpropylammoniumC₄₉H₉₄NO₈P (856.26) 94)1-Erucoyl-2-oleoyl-sn-glycero-3-phospho-N,N,N-tri- methylbutylammoniumC₅₀H₉₆NO₈P (870.28) 95)1-Erucoyl-2-oleoyl-sn-glycero-3-phospho-N,N,N-tri- methylhexylammoniumC₅₂H₁₀₀NO₈P (898.34) 96)1-Nervonoyl-2-lauroyl-sn-glycero-3-phospho-N,N,N-tri-methylpropylammonium C₄₅H₈₈NO₈P (802.16) 97)1-Nervonoyl-2-oleoyl-sn-glycero-3-phospho-N,N,N-tri-methylpropylammonium C₅₁H₉₈NO₈P (884.31)2) Solubilizers

It has emerged that certain substances from the compounds presentedherein, especially those which are soluble in ethanol, are excellentsolubilizers for substances of low solubility in water. Thus, forexample, Taxol can be converted in a simple manner into a form which canbe administered intravenously. Likewise, for example Taxotere,cyclosporin, cholesterol and derivatives thereof, steroids, cortisoneand analogues, erucylphosphocholine (dissolving of the gel-likestructures) have proved to be readily soluble.

In particular, substances which have proved useful for this are thosehaving a distance of 3 C atoms between phosphate and ammonium (n=3 inthe general formula I), for example the substances from Examples 14, 85,111, 139, 144, 176. Outstandingly suitable for these purposes is asimple substance1-erucoyl-1,3-propane-diol-phospho-N,N,N-trimethylpropylammonium (176).This substance can be prepared simply and in high yields on the tonnagescale.

The solubilizers are preferably single-chain compounds, that is to saywhen A=a one of R₁ and R₂ is hydrogen or an alkyl with 1 to 3 C atoms.

Taxol for Intravenous Administration

A solution is prepared from 0.3 g of Taxol and 1.75 g of substance No.176 in 7.95 g of absolute ethanol. The solution is sterilized byfiltration and stored at 4° C. until used.

For intravenous administration, the stock solution is diluted 1:10 or1:100 with physiological saline.

Examples of Single-chaingycerophospho-N,N-dimethyl-N-dihydroxypropylalkylammonium Compounds

(A = a; n = 2-6; R₃, CH₃; m = 1, x = 0, y = 1, z = 1)

98) 1-Palmitoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-eth-ylammonium (n = 2) C₂₆H₅₄NO₉P (555.69) 99)1-Stearoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-eth- ylammonium (n= 2) C₂₈H₅₈NO₉P (583.74) 100)1-Arachinoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-eth- ylammonium(n = z) C₃₀H₆₂NO₉P (611.79) 101)1-Behenoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-eth- ylammonium (n= 2) C₃₂H₆₆NO₉P (639.85) 102)1-Erucoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-eth- ylammonium (n= 2) C₃₂H₆₄NO₉P (637.83) 103)1-Nervonoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-eth- ylammonium(n = 2) C₃₄H₆₈NO₉P (665.88) 104)1-0-Hexadecyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-eth- ylammonium(n = 2) 105)1-0-Octadecyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-eth- ylammonium(n = 2) C₂₈H₆₀NO₈P (569.76) 106)1-0-Eicosanyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-eth- ylammonium(n = 2) C₃₀H₆₄NO₈P (597.81) 107)1-0-Behenyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-eth- ylammonium(n = 2) C₃₂H₆₈NO₈P (625.86) 108)1-Palmitoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-pro- pylammonium(n = 3) C₂₇H₅₆NO₉P (569.71) 109)1-Stearoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-pro- pylammonium(n = 3) C₂₉H₆₀NO₉P (597.77) 110)1-Behenoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-pro- pylammonium(n = 3) C₃₃H₆₈NO₉P (653.87) 111)1-Erucoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-pro- pylammonium (n= 3) C₃₃H₆₆NO₉P (651.86) 112)1-Nervonoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-pro- pylammonium(n = 3) C₃₅H₇₀NO₉P (679.91) 113)1-Stearoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-bu- tylammonium (n= 4) C₃₀H₆₂NO₉P (611.79) 114)1-Erucoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-bu- tylammonium (n= 4) C₃₄H₆₈NO₉P (665.88) 115)1-Stearoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-hexyl- ammonium (n= 6) C₃₂H₆₆NO₉P (639.85) 116)1-Erucoyl-sn-glycero-3-phospho-N,N-dimethyl-N-(diHP)-hexyl- ammonium (n= 6) C₃₆H₇₂NO₈P (693.94)

Examples of Single-chainglycerophospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)alkylammoniumCompounds

(A = 0; n = 2-6; R₃, CH₃; m = 1; x = 0; y = 1; z = 2) Formula I

117) 1-Stearoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁—diHP₂)-ethylammonium (n = 2) C₃₁H₆₄NO₁₁P (657.82) 118)1-Arachinoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁—diHP₂)-ethylammonium (n = 2) C₃₃H₆₈NO₁₁P (685.87) 119)1-Erucoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁—diHP₂)-ethylammonium (n = 2) C₃₅H₇₀NO₁₁P (711.91) 120)1-Nervonoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁—diHP₂)-ethylammonium (n = 2) C₃₇H₇₄NO₁₁P (739.96) 121)1-0-Octadecyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁—diHP₂)-ethylammonium (n = 2) C₃₁H₆₆NO₁₀P (643.83) 122)1-0-Behenyl-sn-glycero-3-phospho-N,N-dimeth-yl-N-(HP₁—diHP₂)-ethylammonium (n = 2) C₃₅H₇₄NO₁₀P (699.94) 123)1-Stearoyl-sn-glycero-3-phospho-N,N-di-methyl-N—(HP₁—diHP₂)-propylammonium (n = 3) C₃₂H₆₆NO₁₁P (671.84) 124)1-Erucoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁—diHP₂)-propylammonium (n = 3) C₃₆H₇₂NO₁₁P (725.94) 125)1-Erucoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁—diHP₂)-butylammonium (n = 4) C₃₇H₇₄NO₁₁P (739.98) 126)1-Erucoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁—diHP₂)-hexylammonium (n = 6) C₃₉H₇₈NO₁₁P (768.04) 127)1-Nervonoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁—diHP₂)-propylammonium (n = 3) C₃₈H₇₆NO₁₁P (754.01) 128)1-Nervonoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁—diHP₂)-butylammonium (n = 4) C₃₉H₇₈NO₁₁P (768.04)

Examples of Single-chainglycerophospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-2-hydroxypropyl-3,1-O,O-dihydroxypropyl)alkylammoniumCompounds

(A = a; n = 2-6; R₃, CH₃; n = 1; x = 0; y = 1; z = 3) Formula I

129) 1-Stearoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁-HP₂—diHP₃)-ethylammonium (n = 2) C₃₄H₇₀NO₁₃P (731.90) 130)1-Erucoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁-HP₂—diHP₃)-ethylammonium (n = 2) C₃₈H₇₆NO₁₃P (785.99) 131)1-Nervonoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁-HP₂—diHP₃)-ethylammonium (n = 2) C₄₀H₈₀NO₁₃P (814.04) 132)1-Erucoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁-HP₂—diHP₃)-propylammonium (n = 3) C₃₉H₇₈NO₁₃P (800.01) 133)1-Nervonoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁-HP₂—diHP₃)-propylammonium (n = 3) C₄₁H₈₂NO₁₃P (828.07) 134)1-Erucoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁-HP₂—diHP₃)-butylammonium (n = 4) C₄₀H₈₀NO₁₃P (814.04) 135)1-Erucoyl-sn-glycero-3-phospho-N,N-dimeth-yl-N—(HP₁-HP₂—diHP₃)-hexylammonium (n = 6) C₄₂H₈₄NO₁₃P (842.09)

Examples of Single-chain Glycerophospho Compounds not Hydroxylated onthe Nitrogen

(A = a; n = 3; R₃, CH₃; m = 1; x = 1; z = 0) Formula I

136) 1-Palmitoyl-sn-glycero-3-phospho-N,N,N-trimethyl-pro- pylammonium(n = 3) C₂₅H₅₂NO₇P (509.66) 137)1-Stearoyl-sn-glycero-3-phospho-N,N,N-trimethyl-pro- pylammonium (n = 3)C₂₇H₅₆NO₇P (537.71) 138)1-Behenoyl-sn-glycero-3-phospho-N,N,N-trimethyl-pro- pylammonium (n = 3)C₃₂H₆₄NO₂P (593.82) 139)1-Erucoyl-sn-glycero-3-phospho-N,N,N-trimethyl-pro- pylammonium (n = 3)C₃₁H₆₂NO₇P (591.81) 140)1-Nervonoyl-sn-glycero-3-phospho-N,N,N-trimethyl-pro- pylammonium (n =3) C₃₃H₆₆NO₇P (619.86)

Examples ofω,ω′-alkanediol-phospho-N,N-dimethyl-N-di-hydroxypropylalkylammoniumCompounds

(A = b; n = 2-4; R₃, CH₃; m = 1; x = 0; y = 1; z = 1) Formula I

141) 1-Stearoyl-ethylene glycol-phospho-N,N-di-methyl-N-dihydroxypropylethylammonium (n = 2) C₂₇H₅₆NO₈P (553.71) 142)1-Behenoyl-1,3-propanediol-phospho-N,N-dimethyl-N-di-hydroxypropylethylammonium (n = 2) C₃₂H₆₆NO₈P (623.85) 143)1-Stearoyl-1,3-propanediol-phospho-N,N-dimethyl-N-di-hydroxypropylethylammonium (n = 2) C₂₈H₅₈NO₈P (567.74) 144)1-Erucoyl-1,3-propanediol-phospho-N,N-dimethyl-N-di-hydroxypropylethylammonium (n = 2) C₃₂H₆₄NO₈P (621.83) 145)1-Erucoyl-1,3-propanediol-phospho-N,N-dimethyl-N-di-hydroxypropylpropylammonium (n = 3) C₃₃H₆₆NO₈P (635.86) 146)1-Erucoyl-1,3-propanediol-phospho-N,N-dimethyl-N-di-hydroxypropylbutylammonium (n = 4) C₃₄H₆₈NO₈P (649.88)

Examples of1,2-alkanediol-phospho-N,N-dimethyl-N-di-hydroxypropylalkylammoniumCompounds

(A = b; n = 2-4; R₃, CH₃; m = 1; x = 0; y = 1; z = 1) Formula I

147) 2-Erucoyl-1,2-propanediol-phospho-N,N-dimethyl-N-dihydroxypropylethylammonium C₃₂H₆₄NO₈P    (621.33) 148)1-Erucoyl-1,2-propanediol-phospho-N,N-dimethyl-N-dihydroxypropylethylammonium C₃₂H₆₄NO₈P    (621.33) 149)2-Erucoyl-1,2-propanediol-phospho-N,N-dimethyl-N-dihydroxypropylpropylammonium C₃₃H₆₆NO₈P    (635.86) 150)1-Erucoyl-1,2-propanediol-phospho-N,N-dimethyl-N-dihydroxypropylbutylammonium C₃₄H₆₈NO₈P    (649.88)

Examples ofω,ω′-alkanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl)-3,1-O,O-dihydroxropyl)alkylammoniumCompounds

(A = b; n = 2-4; R₃, CH₃; m = 1, x = 0; y = 1; z = 2) Formula I

151) 1-Stearoyl-ethylene glycol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O- dihydroxypropyl)ethylammoniumC₃₀H₆₂NO₁₀P    (627.79) 152)1-Behenoyl-1,3-propanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)ethyl- ammoniumC₃₅H₇₂NO₁₀P    (697.93) 153)1-Stearoyl-1,3-propanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl)-3,1-O,O-dihydroxypropylethyl- ammoniumC₃₁H₆₄NO₁₀P    (641.82) 154)1-Erucoyl-1,3-propanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)ethyl- ammnoniumC₃₅H₇₀NO₁₀P    (695.91) 155)1-Erucoyl-1,3-propanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)propyl- ammoniumC₃₆H₇₂NO₁₀P    (709.94) 156)1-Erucoyl-1,3-propanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)butyl- ammoniumC₃₇H₇₄NO₁₀P    (723.96) 157)1-Erucoyl-1,4-butanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)propyl- ammoniumC₃₇H₇₄NO₁₀P    (723.96) 158)1-Erucoyl-1,6-hexanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)propyl- ammoniumC₃₉H₇₈NO₁₀P    (752.02) 159)1-Erucoyl-1,8-octanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl)-3,1-O,O-dihydroxypropyl)propyl- ammoniumC₄₁H₈₂NO₁₀P    (780.07)

Examples of1,2-alkanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)alkylammoniumCompounds

(A = b; n = 2-4; R₃, CH₃; m = 1; x = 0; y = 1; z − 2) Formula I

160) 2-Erucoyl-1,2-propanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)ethyl- ammoniumC₃₅H₇₀NO₁₀P    (695.91) 161)1-Erucoyl-1,2-propanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)ethyl- ammoniumC₃₅H₇₀NO₁₀P    (695.91) 162)2-Erucoyl-1,2-propanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)propyl- ammoniumC₃₆H₇₂NO₁₀P    (709.94) 163)1-Erucoyl-1,2-propanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)butyl- ammoniumC₃₇H₇₄NO₁₀P    (723.96) 164)1-Erucoyl-1,2-butanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)propyl- ammoniumC₃₇H₇₄NO₁₀P    (723.96) 165)1-Erucoyl-1,2-hexanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)propyl- ammoniumC₃₉H₇₈NO₁₀P    (752.02) 166)1-Erucoyl-1,2-octanediol-phospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-dihydroxypropyl)propyl- ammoniumC₄₁H₈₂NO₁₀P    (780.07)

Examples ofω,ω′-alkanediol-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-2-hydroxypropyl-3,1-O,O-dihydroxypropyl)alkylammoniumCompounds

(A = b; n = 2-6; R, CH₃; m = 1; x = 0; y = 1; z = 3) Formula I

167) 1-Oleoyl-ethylene glycol-phospho-N,N-dimethyl-N—(HP₁—HP₂-diHP₃)-ethylammonium C₃₄H₆₈NO₁₂P    (713.88) 168)1-Erucoyl-1,3-propanediol-phospho-N,N-dimethyl-N—(HP₁—HP₂-diHP₃)-ethylammonium C₃₈H₇₆NO₁₂P    (769.99) 169)1-Oleoyl-1,3-propanediol-phospho-N,N-dimethyl-N—(HP₁—HP₂-diHP₃)-propylammonium C₃₅H₇₀NO₁₂P    (727.91) 170)1-Erucoyl-1,3-propanediol-phospho-N,N-dimethyl-N—(HP₁—HP₂-diHP₃)-propylammonium C₃₉H₇₈NO₁₂P    (784.01) 171)1-Erucoyl-1,3-propanediol-phospho-N,N-dimethyl-N—(HP₁—HP₂-diHP₃)-butylammonium C₄₀H₈₀NO₁₂P    (798.04) 172)1-Erucoyl-1,3-propanediol-phospho-N,N-dimethyl-N—(HP₁—HP₂-diHP₃)-hexylammonium C₄₂H₈₄NO₁₂P    (826.10) (Abbreviation:HP = 2-Hydroxypropyl diHP = Dihydroxypropyl)

Examples of Alkanediol-phospho Compounds not Hydroxylated on theNitrogen

(A = b; n = 2-6; R, CH₃; m = 1; x = 1; z = 0) Formula I

173) 1-Erucoyl-ethylene glycol-phospho-N,N,N- trimethylpropylammoniumC₃₀H₆₀NO₆P    (561.78) 174) 1-Arachinoyl-1,3-propanediol-phospho-N,N,N-trimethylpropylammonium C₂₉H₆₉NO₆P    (549.77) 175)1-Stearoyl-1,3-propanediol-phospho-N,N,N- trimethylpropylammoniumC₂₇H₅₆NO₆P    (521.71) 176)1-Erucoyl-1,3-propanediol-phospho-N,N,N-trimethyl- propylammoniumC₃₁H₆₂NO₆P    (575.81) 177)1-Erucoyl-1,3-propanediol-phospho-N,N,N-trimethyl- butylammoniumC₃₂H₆₄NO₆P    (589.83) 178)1-Erucoyl-1,3-propanediol-phospho-N,N,N-trimethyl- pentylammoniumC₃₃H₆₆NO₆     (603.86) 179)1-Erucoyl-1,2-propanediol-phospho-N,N,N-trimethyl- propylammoniumC₃₁H₆₂NO₆P    (575.81) 180)2-Erucoyl-1,2-propanediol-phospho-N,N,N-trimethyl- propylammoniumC₃₁H₆₂NO₆P    (575.81) 181)1-Erucoyl-1,2-propanediol-phospho-N,N,N-trimethyl- butylammoniumC₃₂H₆₄NO₆P    (589.83) 182)1-Erucoyl-1,2-propanediol-phospho-N,N,N-trimethyl- hexylammoniumC₃₄H₆₈NO₆P    (617.92)3) Active Ingredients

It was found in earlier investigations that alkylphosphocholines haveantitumour activity only when the phosphate-ammonium distance is two Catoms, that is to say corresponds to phosphocholine (n=2 in the generalformula I). Compounds with a distance of n⁻>2 had no activity. Theactive ingredients were administered orally in these earlierinvestigations.

We have now found, surprisingly, that erucyl-phospho compounds withphosphate-ammonium distances of >2 have excellent antitumour activitywhich is in fact superior to that of alkylphosphocholines when thesesubstances are administered intravenously, as the following comparisonshows:

Erucylphosphocholine (n=2 in general formula I) The substance formsgel-like structures in water and therefore can be administeredintravenously only with difficulty in relatively high concentrations.Erucylphosphocholine has only a slight long-term effect in the animalmodel of methylnitrosourea-induced mammary carcinoma. Tumour growth isobserved again only 7 days after discontinuation of the therapy.

Erucylphospho-N,N,N-trimethylprorylammonium (n=3)

The substance is readily soluble in water, forms no gels and can beadministered intravenously without difficulty. It can therefore also beused as solubilizer. However, its long-term effect in the above animalmodel is particularly noteworthy and impressive. No new tumour growth isobserved even 4 weeks after discontinuation of the therapy.

Examples of alkylphospho-N,N,N-dimethyl-N-dihydroxy-propylalkylammoniumCompounds

(A = c; n = 2-6; R₃, CH₃; m = 1; x = 0; y = 1; z = 1) Formula I

183) Hexadecylphospho-N,N-dimethyl-N-dihydroxypropyl- ethylammoniumC₂₃H₅₀NO₆P    (467.62) 184)Octadecylphosho-N,N-dimethyl-N-dihydroxypropyl- ethylammoniumC₂₅H₅₄NO₆P    (495.68) 185)Erucylphospho-N,N-dimethyl-N-dihydroxypropyl- ethylammoniumC₂₉H₆₀NO₆P    (549.77) 186)Erucylphospho-N,N-dimethyl-N-dihydroxypropyl- propylammoniumC₃₀H₆₂NO₆P    (563.80) 187)Erucylphospho-N,N-dimethyl-N-dihydroxypropyl- butylammoniumC₃₁H₆₄NO₆P    (577.82) 188)Erucylphospho-N,N-dimethyl-N-dihydroxypropyl- hexylammoniumC₃₃H₆₈NO₆P    (605.88) 189) Oleylphospho-N,N-dimethyl-N-dihydroxypropyl-ethylammonium C₂₅H₅₂NO₆P    (493.66) 190)Oleylphospho-N,N-dimethyl-N-dihydroxypropyl- propylammoniumC₂₆H₅₄NO₆P    (507.69) 191) Oleylphospho-N,N-dimethyl-N-dihydroxypropyl-butylammonium C₂₇H₅₆NO₆P    (521.21) 192)(Z-11)-Eicosenylphospho-N,N-dimethyl-N-dihydroxy- propyl-ethylammoniumC₂₇H₅₆NO₆P    (521.21) 193)(Z-11)-Eicosenylphospho-N,N-dimethyl-N-dihydroxy- propyl-propylammoniumC₂₈H₅₈NO₆P    (535.74) 194)(Z-11)-Eicosenylphospho-N,N-dimethyl-N-dihydroxy- propyl-butylammoniumC₂₉H₆₀NO₆P    (549.77) 195)(Z-11)-Eicosenylphospho-N,N-dimethyl-N-dihydroxy- propyl-pentylammoniumC₃₀H₆₂NO₆P    (563.80) 196)(Z-11)-Eicosenylphospho-N,N-dimethyl-N-dihydroxy- propyl-hexylammoniumC₃₁H₆₄NO₆P    (577.82)

Examples ofalkylphospho-N,N-dimethyl-N-(2-hydroxypropyl-1,2-dihydroxypropyl)alkylammonium

(A = c; n = 2-6; R₃, CH₃; m = 1; x = 0; y = 1; z = 2) Formula I

197) Hexadecyl-phospho-N,N-dimethyl-N—(HP₁-diHP₂)-ethyl- ammoniumC₂₆H₅₆NO₈P    (541.70) 198)Octadecyl-phospho-N,N-dimethyl-N—(HP₁-diHP₂)-ethyl- ammoniumC₂₈H₆₀NO₈P    (569.76) 199)Erucyl-phospho-N,N-dimethyl-N—(HP₁-diHP₂)-ethyl- ammoniumC₃₂H₆₆NO₈P    (623.85) 200)Erucyl-phospho-N,N-dimethyl-N—(HP₁—diHP₂)-propyl- ammoniumC₃₃H₆₈NO₈P    (637.87) 201)Erucyl-phospho-N,N-dimethyl-N—(HP₁-diHP₂)-butyl- ammoniumC₃₄H₇₀NO₈P    (651.90) 202)Erucyl-phospho-N,N-dimethyl-N—(HP₁—diHP₂)-hexyl- ammoniumC₃₆H₇₄NO₈P    (679.95) 203)Oleyl-phospho-N,N-dimethyl-N—(HP₁-diHP₂)-ethyl- ammoniumC₂₈H₅₈NO₈P    (567.74) 204)Oleyl-phospho-N,N-dimethyl-N—(HP₁-diHP₂)-propyl- ammoniumC₂₉H₆₀NO₈P    (581.77) 205)Oleyl-phospho-N,N-dimethyl-N—(HP₁-diHP₂)-butyl- ammoniumC₃₀H₆₂NO₈P    (595.79) 206) (Z-11)-Eicosenyl-phospho-N,N-dimethyl-N—(HP₁—diHP₂)-ethylammonium C₃₀H₆₂NO₈P    (595.79) 207)(Z-11)-Eicosenyl-phospho-N,N-dimethyl- N—(HP₁—diHP₂)-propylammoniumC₃₀H₆₄NO₆P    (609.82) 208) (Z-11)-Eicosenyl-phospho-N,N-dimethyl-N—(HP₁—diHP₂)-butylammonium C₃₂H₆₆NO₈P    (623.85)

Examples ofalkylphospho-N,N-dimethyl-N-(2-hydroxypropyl-3,1-O,O-hydroxypropyl-3,1-O,O-1,2-dihydroxypropyl)alkylammoniumCompounds

(A = c; n = 2-4; R₃, CH₃; m = 1; x = 0; y = 1; z = 3) Formula I

209) Hexadecyl-phospho-N,N-dimethyl-N—(HP₁—HP₂-diHP₃)- ethylammoniumC₂₉H₆₂NO₁₀P    (615.78) 210)Octadecyl-phospho-N,N-dimethyl-N—(HP₁—HP₂-diHP₃)- ethylammoniumC₃₁H₆₆NO₁₀P    (643.83) 211)Oleol-phospho-N,N-dimethyl-N—(HP₁—HP₂-diHP₃)-ethyl- ammoniumC₃₁N₆₄NO₁₀P    (641.82) 212)(Z-11)-Eicosenyl-phospho-N,N-dimethyl-N—(HP₁—HP₂- diHP₃)-ethylammoniumC₃₃H₆₈NO₁₀P    (669.87) 213)(Z-11)-Eicosenyl-phospho-N,N-dimethyl-N—(HP₁—HP₂- diHP₃)-propylammoniumC₃₄H₇₀NO₁₀P    (683.90) 214)(Z-11)-Eicosenyl-phospho-N,N-dimethyl-N—(HP₁—HP₂- diPH₃)-butylammoniumC₃₅H₇₂NO₁₀P    (697.93) 215)Erucyl-phospho-N,N-dimethyl-N—(HP₁—HP₂-diHP₃)- ethylammoniumC₃₅H₇₂NO₁₀P    (697.93) 216)Erucyl-phospho-N,N-dimethyl-N—(HP₁—HP₂-diHP₃)- propylammoniumC₃₆H₇₄NO₁₀P    (711.95)

Examples of Alkylphospho Compounds Having no Dihydroxyalkyl Radicals onthe Nitrogen

(A = a; n = 3-6; R₃, CH₃; m = 1, x = 1-3; z = 0)

217) Erucyl-phospho-N,N,N-trimethyl-propylammoniumC₂₈H₅₈NO₄P    (503.74) 218)Erucyl-phospho-N,N-dimethyl-N-ethyl-propylammoniumC₂₉H₆₀NO₄P    (517.77) 219) Erucyl-phospho-N,N-dimethyl-N-propyl-propyl-ammonium C₃₀H₆₂NO₄P    (531.80) 220)Erucyl-phospho-N,N-dimethyl-N-allyl-propylammoniumC₃₀H₆₀NO₄P    (529.78) Rf values of substances 217-240 in the systemdescribed: Rf 0.30-0.40 221) (Z)-10-Docosenyl-2-phospho-N,N,N-trimethyl-propylammonium C₂₈H₅₈NO₄P    (503.74) 222)(Z)-10-Docosenyl-2-phospho-N,N-dimethyl-N-ethyl- propylammoniumC₂₉H₆₀NO₄P    (517.77) 223) Erucyl-phospho-N,N N-trimethyl-butylammoniumC₂₉H₆₀NO₄P    (517.77) 224)Erucyl-phospho-N,N-dimethyl-N-ethyl-butylammonium C₃₀H₆₂NO₄P    (531.80)225) Erucyl-phospho-N,N-dimethyl-N-propyl-butylammoniumC₃₁H₆₄NO₄P    (545.82) 226) (Z)-10-Docosenyl-2-phospho-N,N,N-trimethyl-butylammonium C₂₉H₆₀NO₄P    (517.77) 227)(Z)-11-Eicosenyl-phospho-N,N,N-trimethyl- propylammoniumC₂₆H₅₄NO₄P    (475.69) 228)(Z)-11-Eicosenyl-phospho-N,N-dimethyl-N-ethyl- propylammoniumC₂₇H₅₆NO₄P    (489.72) 229)(Z)-11-Eicosenyl-phospho-N,N-diethyl-N-methyl- propylammoniumC₂₈H₅₈NO₄P    (503.74) 230)(Z)-11-Eicosenyl-phospho-N,N-dimethyl-N-propyl- propylammoniumC₂₈H₅₈NO₄P    (503.74) 231) (Z)-11-Eicosenyl-phospho-N,N,N-trimethyl-butylammonium C₂₇H₅₆NO₄P    (489.72) 232)(Z)-11-Eicosenyl-phospho-N,N-dimethyl-N-ethyl- butylammoniumC₂₈H₅₈NO₄P    (503.74) 233)(Z)-11-Eicosenyl-phospho-N,N-dimethyl-N-propyl- butylammoniumC₂₉H₆₀NO₄P    (517.77) 234)(Z)-11-Eicosenyl-phospho-N,N-dimethyl-N-alkyl- butylammoniumC₂₉H₅₈NO₄P    (575.75) 235) Oleyl-phospho-N,N,N-trimethyl-propylammoniumC₂₄H₅₀NO₄P    (447.64) 236)Oleyl-phospho-N,N-dimethyl-N-ethyl-propylammonium C₂₅H₅₂NO₄P    (461.66)237) Oleyl-phospho-N,N-dimethyl-N-propylene-propyl- ammoniumC₂₆H₅₄NO₄P    (475.69) 238) Oleyl-phospho-N,N,N-trimethyl-butylammoniumC₂₅H₅₂NO₄P    (461.66) 239)Oleyl-phospho-N,N-dimethyl-N-ethyl-butylammonium C₂₆H₅₄NO₄P    (475.69)240) Oleyl-phospho-N,N-dimethyl-N-propyl-butylammoniumC₂₇H₅₆NO₄P    (489.72)Active Ingredients Based on Alkylated(ether)Lysolecithins andHydroxylated on the Nitrogen

(A = a; n = 2-4; R₃, CH₃; m = 1; x = 0; y = 1; z = 1-2) Formula I

241) 1-0-Octadecyl-2-0-methyl-sn-glycero-3-phospho-N,N-dimethyl-N-dihydroxypropyl-ethylammonium (n = 2)C₂₉H₆₂NO₈P    (583.78) 242)3-0-Octadecyl-2-0-methyl-sn-glycero-1-phospho-N,N-dimethyl-N-dihydroxypropyl-ethylammonium (n = 2)C₂₉H₆₂NO₈P    (583.78) 243)1-0-Octadecyl-2-0-tert-butyl-sn-glycero-3-phospho-N,N-dimethyl-N-dihydroxypropyl-ethylammonium (n = 2)C₃₂H₆₈NO₈P    (625.86) 244)3-0-Octadecyl-2-0-tert-butyl-sn-glycero-3-phospho-N,N-dimethyl-N-dihydroxypropyl-ethylammonium (n = 2)C₃₂H₆₈NO₈P    (625.86) 245)1-0-Octadecyl-2-0-methyl-sn-glycero-3-phospho-N,N-dimethyl-N-dihydroxypropyl-propylammonium (n = 3)C₃₀H₆₄NO₈P    (597.81) 246)1-0-Octadecyl-2-0-methyl-sn-glycero-3-phospho-N,N-dimethyl-N-dihydroxypropyl-butylammonium (n = 4)C₂₁H₆₆NO₈P    (611.84) 247) 1-0-Erucyl-2-0-methyl-sn-glycero-3-phospho-N,N-dimethyl-N-dihydroxypropyl-ethylammonium (n = 2)C₃₃H₆₈NO₈P    (637.87) 248) 1-0-Erucyl-2-0-methyl-sn-glycero-3-phospho-N,N-dimethyl-N-dihydroxypropyl-propylammonium (n = 3)C₃₄H₇₀NO₈P    (651.90) 249)1-0-Octadecyl-2-0-methyl-sn-glycero-3-phospho-N,N-dimethyl-N—(HP₁-diHP₂)-ethylammonium (n = 2) C₃₂H₆₈NO₁₀P    (657.86)250) 1-0-Octadecyl-2-0-tert-butyl-sn-glycero-3-phospho-N,N-dimethyl-N—(HP₁-diHP₂)-ethylammonium (n = 2) C₃₅H₇₄NO₁₀P    (699.94)251) 1-0-Octadecyl-2-0-methyl-sn-glycero-3-phospho-N,N-dimethyl-N—(HP₁-diHP₂)-propylammonium (n = 3)C₃₃H₇₀NO₁₀P    (671.89) 252)1-0-Octadecyl-2-0-tert-butyl-sn-glycero-3-phospho-N,N-dimethyl-N—(HP₁-diHP₂)-propylammonium (n = 3)C₃₆H₇₆NO₁₀P    (713.97) 253)1-0-Octadecyl-2-0-tert-butyl-sn-glycero-3-phospho-N,N-dimethyl-N—(HP₁-diHP₂)-butylammonium (n = 4) C₃₇H₇₈NO₁₀P    (727.99)254) 1-0-Erucyl-2-0-methyl-sn-glycero-3-phospho-N,N-dimethyl-N—(HP₁-diHP₂)-butylammonium (n = 4) C₃₈H₇₈NO₁₀P    (739.01)Active Ingredients Based on Alkylated(ether)Lysolecithins and notHydroxylated on the Nitrogen

(A = a; n = 3, 4; R₃, CH₃; m = 1; x = 1; z = 0) Formula I

255) 1-0-Erucyl-2-0-methyl-sn-glycero-3-phospho-N,N,N-trimethyl-propylammonium (n = 3) C₃₂H₆₆NO₆P  (591.85) 256)1-0-Erucyl-3-O-methyl-sn-glycero-2-phospho-N,N,N-trimethyl-propylammonium (n = 3) C₃₂H₆₆NO₆P  (591.85) 257)1-0-(Z)-11-Eicosenyl-2-0-methyl-sn-glycero-3-phospho-N,N,N-trimethyl-propylammonium (n = 3) C₃₀H₆₂NO₆P  (563.80)258) 1-0-(Z)-11-Eicosenyl-2-0-tert-butyl-sn-glycero-3-phospho-N,N,N-trimethyl-propylammonium (n = 3) C₃₃H₆₈NO₆P  (605.88)259) 1-0-Oleyl-2-0-tert-butyl-sn-glycero-3-phospho-N,N,N-trimethyl-propylammonium (n = 3) C₃₁H₆₄NO₆P  (577.82) 260)1-0-(Z)-11-Eicosenyl-2-0-tert-butyl-sn-glycero-3-phospho-N,N,N-butylammonium (n = 4) C₃₄H₇₀NO₆P  (619.90) 261)1-0-Oleyl-2-0-tert-butyl-sn-glycero-3-phospho-N,N,N-trimethyl-butylammonium (n = 4) C₃₂H₆₆NO₆P  (591.85)Active Ingredients Based on Alkanediol-phospho Compounds andHydroxylated on the Nitrogen

(A = b; n = 2, 3; R₃, CH₃; m = 1; x = 0; y = 1; z = 1) Formula I

262) 1-0-Erucyl(ethylene glycol)phospho-N,N-dimethyl-N-dihydroxypropylethylammonium C₃₁H₆₄NO₇P  (593.82) 263)1-0-Erucyl-1,3-propanediol-phospho-N,N-dimethyl-N-dihydroxypropylethylammonium C₃₂H₆₆NO₇P  (607.85) 264)1-0-Erucyl-1,2-propanediol-phospho-N,N-dimethyl-N-dihydroxypropylethylammonium C₃₂H₆₆NO₇p  (607.85) 265)2-0-Erucyl-1,2-propanediol-phospho-N,N-dimethyl-N-dihydroxypropylethylammonium C₃₂H₆₆NO₇P  (607.85) 266)1-0-(Z)-11-Eicosenyl-1,2-propanediol-phospho-N,N-dimethyl-N-dihydroxypropylethylammonium C₃₀H₆₂NO₇P  (579.49) 267)2-0-(Z)-11-Eicosenyl-1,2-propanediol-phospho-N,N-dimethyl-N-dihydroxypropylethylammonium C₃₀H₆₂NO₇P  (579.49) 268)1-0-Oleyl-1,2-Propanediol-phospho-N,N-dimethyl-N-dihydroxypropylethylammonium C₂₈H₅₈NO₇P  (551.74) 269)2-0-Oleyl-1,2-propanediol-phospho-N,N-dimethyl-N-dihydroxypropylethylammonium C₂₈H₅₈NO₇P  (551.74) 270)2-0-Octadecyl-1,2-propanediol-phospho-N,N-dimethyl-N-dihydroxypropylethylammonium C₂₉H₆₂NO₇P  (553.76) 271)1-0-Octadecyl-1,2-propanediol-phospho-N,N-dimethyl-N-dihydroxypropylpropylammonium C₂₉H₆₂NO₇P  (626.24) 272)2-0-Octadecyl-1,2-propanediol-phospho-N,N-dimethyl-N-dihydroxypropylpropylammonium C₂₉H₆₂NO₇P  (626.24)Active Ingredients Based on alkanediol-phospho Compounds and notHydroxylated on the Nitrogen

(A = b; n = 3; R₃, CH₃; m = 1; x = 1; z = 0) Formula I

273) 1-0-Erucyl-1,2-propanediol-phospho-N,N,N-tri- methylpropylammoniumC₃₁H₆₄NO₅P  (562.82) 274) 1-0-Erucyl-1,2-propanediol-phospho-N,N,N-tri-methylpropylammonium C₃₁H₆₄NO₅P  (562.82) 275)1-0-(Z)-11-Eicosenyl-1,3-propanediol-phospho-N,N,N-trimethylpropylammonium C₂₉H₆₀NO₅P  (533.77) 276)1-0-Oleyl-1,2-propanediol-phospho-N,N,N-trimethyl- propylammoniumC₂₇H₅₆NO₅P  (505.72) 277)2-0-Oleyl-1,2-propanediol-phospho-N,N,N-trimethyl- propylammoniumC₂₇H₅₆NO₅P  (505.72) 278) 1-0-Octadecyl-1,2-propanediol-phospho-N,N,N-propylammonium C₂₇H₅₈NO₅P  (507.73) 279)2-0-Octadecyl-1,2-propanediol-phospho-N,N,N- trimethylpropylammoniumC₂₇H₅₈NO₅P  (507.73)

1. A pharmaceutical composition comprising a water-insolublepharmaceutically active ingredient and a compound represented byStructural Formula (I):

in which A is:

wherein: R₁ and R₂ are, independently of one another, hydrogen, asaturated or unsaturated, branched or unbranched, substituted orunsubstituted acyl or alkyl radical, wherein the total number of carbonatoms in R₁ and R₂ combined is from 16 to 44 carbon atoms; m is 1 or 2;n is an integer from 2 to 8; R₃ is: a) 1,2-hydroxypropyl, or b)alkylwith 1 to 3 carbon atoms when z is greater than 0, or c)alkyl with 1 to3 carbon atoms when n is not 2 and z is 0; x is an integer from 0 to 8;y is 1 when z is 2 to 5 and y is from 1 to 4 when z is 1; and z is aninteger from 0 to
 5. 2. The pharmaceutical composition of claim 1,further comprising a pharmaceutically acceptable solvent.
 3. Thepharmaceutical composition of claim 2, wherein the pharmaceuticallyacceptable solvent is physiological saline.
 4. The pharmaceuticalcomposition of claim 1, wherein the active ingredient requiressolubilization.
 5. The pharmaceutical composition of claim 4, whereinthe active ingredient is selected from the group consisting of taxol,taxotere, cyclosporin, cholesterol and derivatives thereof, steroids,cortisone and analogues thereof, and erucylphosphocholine.
 6. Thepharmaceutical composition of claim 1, wherein the active ingredient isselected from the group consisting of a cytostatic, an immunomodulatingsubstance, and a lytic agent.
 7. The pharmaceutical composition of claim1, wherein: n=3; R₃ is methyl; m=1; x=0; y=1; z=1; and R₁ and R₂ areeach oleoyl.
 8. The pharmaceutical composition of claim 1, wherein: n=3;R₃ is methyl; m=1; x=1; z=0; and R₁ and R₂ are each oleoyl.
 9. Thepharmaceutical composition of claim 1, wherein: n=3; R₃ is methyl; m=1;x=0; y=1; z=1; R₁ is erucoyl; and R₂=H.
 10. The pharmaceuticalcomposition of claim 1, wherein: n=3; R₃ is methyl; m=1; x=1; z=0; R₁ iserucoyl; and R₂=H.
 11. The pharmaceutical composition of claim 1,wherein n=3.
 12. The composition of claim 11, wherein one of R₁ and R₂is hydrogen or a C1-C3 alkyl group.